Certain arylalkyl or pyridylalkyl hydroxamates useful for treating allergies and asthma

ABSTRACT

Arylhydroxamates are provided having the structure   &lt;IMAGE&gt; wherein R1 is hydrogen, lower alkyl, aryl, lower alkenyl, cycloalkyl, or aralkyl; R2 is hydrogen, lower alkyl, aryl, cycloalkyl, alkanoyl or aroyl; m is 2 to 8; and   &lt;IMAGE&gt;  wherein R3 is OH, COOH &lt;IMAGE&gt;  These compounds are useful as inhibitors of  DELTA 5-lipoxygenase and as such are useful as antiallergy agents.

DESCRIPTION OF THE INVENTION

The present invention relates to arylhydroxamates which are inhibitorsof Δ⁵ -lipoxygenase and as such are useful, for example, as antiallergyagents and for treating bronchial asthma. These compounds have thestructural formula ##STR4## wherein R¹ is hydrogen, lower alkyl, aryl,lower alkenyl, cycloalkyl, or aralkyl;

R² is hydrogen, lower alkyl, cycloalkyl, alkanoyl or aroyl.

m is 2 to 8; and

Z is 2-, 3- or 4-pyridyl or phenyl substituted with OH, COOH or ##STR5##wherein R^(2') can be any of the radicals set out under the definitionof R², and R⁴ is H or lower alkyl.

Thus, the compounds of the invention include the following: ##STR6##wherein R³ is COOH or ##STR7## or OH.

The above compounds will form monobasic or dibasic salts. In addition,the compounds of formula I will form salts with dicyclohexylamine aswell as with tris(hydroxymethyl)aminomethane and other amines as set outin U.S. Pat. No. 4,294,759.

The term "lower alkyl" or "alkyl" as employed herein by itself or aspart of another group includes both straight and branched chain radicalsof up to 12 carbons, preferably 1 to 8 carbons, such as methyl, ethyl,propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl, dodecyl, the various branched chain isomers thereof, and thelike as sell as such groups including a halo-substituent, such as F, Br,Cl or I or CF₃, an alkoxy substituent, an aryl substituent, analkyl-aryl substituent, a haloaryl substituent, a cycloalkylsubstituent, an alkylcycloalkyl substituent, hydroxy, an alkylaminosubstitutent, an alkanoylamino substituent, an arylcarbonylaminosubstituent, a nitro substituent, a cyano substituent, a thiolsubstituent or an alkylthio substituent.

The term "cycloalkyl" employed herein by itself or as part of anothergroup includes saturated cyclic hydrocarbon groups containing 3 to 12carbons, preferably 3 to 8 carbons, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, any of which groups may be substituted with 1 to 2halogens, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, an arylgroup, 1 or 2 hydroxyl groups, 1 or 2 alkylamino groups, 1 or 2alkanoylamino groups, 1 or 2 arylcarbonylamino groups, 1 or 2 aminogroups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groupsand/or 1 or 2 alkylthio groups.

The term "aryl" or "Ar" as employed herein by itself or as part ofanother group refers to monocyclic or bicyclic aromatic groupscontaining from 6 to 10 carbons in the ring portion, such as phenyl,naphthyl, substituted phenyl or substituted naphthyl wherein thesubstituent on either the phenyl or naphthyl may be 1 or 2 lower alkylgroups, 1 or 2 halogens (Cl, Br or F), 1 or 2 lower alkoxy groups, anaryl group, 1 or 2 hydroxyl groups, 1 or 2 alkylamino groups, 1 or 2alkanoylamino groups, 1 or 2 arylcarbonylamino groups, 1 or 2 aminogroups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groupsand/or 1 or 2 alkylthio groups.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used hereinrefers to lower alkyl groups as discussed above having an arylsubstituent, such as benzyl.

The term "lower alkenyl" or "alkenyl" as employed herein by itself or aspart of another group includes an unsaturated hydrocarbon group havingfrom 3 to 8 carbons and a single carbon-carbon double bond, such asethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and thelike.

The term "alkanoyl" or "aroyl" as used herein by itself or as part ofanother group refers to a lower alkyl group or an aryl group linked to acarbonyl group.

The term "halogen" or "halo" as used herein refers to chlorine, bromine,fluorine or iodine with chlorine being preferred.

The term "(CH₂)_(m) " includes a straight or branched chain radicalhaving 1 to 7 carbons in the normal chain and may contain one or twolower alkyl and/or one or two halogen substituents. Examples of(CH₂)_(m) groups include ##STR8## and the like.

Preferred are those compounds of the invention wherein R¹ is alkyl, suchas methyl, R² is H, m is 3 to 5; and Z is ##STR9##

The various compounds of the invention may be prepared as describedbelow.

Compounds of the invention wherein Z is phenyl substituted with anortho--COOH group, that is ##STR10## may be prepared by esterifying ahydroxyalkyl benzene carboxylic acid of the structure A ##STR11## byreacting A with benzylbromide in the presence of base such as sodiumbicarbonate and an inert solvent such as dimethylformamide to form thebenzyl ester B ##STR12##

Ester B is then oxidized by reacting B with pyridinium chlorochromate inthe presence of sodium acetate and methylene chloride to form thealdehyde C ##STR13##

Aldehyde C is next reacted with Wittig reagent D ##STR14## in thepresence of n-butyllithium and an inert solvent such as tetrahydrofuranto form the ester E ##STR15## which is subjected to hydrogenation andhydrogenolysis by treating E with hydrogen in the presence of palladiumon carbon or other catalyst to form the acid F ##STR16##

Acid F is reacted with oxalyl chloride in the presence of benzene,preferably in the presence of some dimethylformamide, to form acidchloride G ##STR17##

Acid chloride G is then converted to the corresponding hydroxamate bytreating G with hydroxylamine H ##STR18## in the presence of an organicbase such as triethylamine and aqueous organic solvent such astetrahydrofuran or 1,2-dimethoxy ethane to form hydroxamate J ##STR19##which is then hydrolyzed by treatment with alkali metal hydroxide suchas NaOH or LiOH in the presence of aqueous alcoholic solvent such asmethanol or ethanol to form the hydroxamate IV.

The starting Wittig reagent D is prepared by esterifying o-toluic acidby treatment with methyl iodide in the presence of sodium bicarbonateand dimethylformamide to form the corresponding methyl ester which isbrominated by treatment with N-bromosuccinimide andazobisisobutyronitrile in benzene to form α-bromo-o-toluic acid methylester. The ester is then treated with triphenylphosphine in the presenceof acetonitrile or benzene to form D.

Compounds of the invention wherein Z is phenyl substituted with apara--COOH group, that is ##STR20## may be prepared by reacting thephosphorus compound K ##STR21## with aldehyde L ##STR22## in a Wittigreaction at reduced temperature in the presence of n-butyllithium andtetrahydrofuran to form the ester M ##STR23##

Ester M is then converted to the corresponding hydroxamate V employingprocedures outlined above in converting ester E to hydroxamate IV.

The starting Wittig reagent K is prepared by esterifyingα-bromo-p-toluic acid by treatment with benzyl alcohol,dicyclohexylcarbodiimide and 4-dimethylamino-pyridine in ether andtetrahydrofuran to form the benzyl ester which is then treated withtriphenylphosphine in benzene to form K.

The aldehyde L may be prepared by oxidizing the alcohol ester L'##STR24## by treatment with pyridinium dichlorochromate in the presenceof methylene chloride.

Compounds of the invention wherein Z is ##STR25## may be prepared bystarting from the aldehyde L and α-bromo-m-toluic acid and following theprocedure set out above for the preparation of V.

Compounds of the invention wherein Z is ##STR26## that is ##STR27## maybe prepared by reacting acid N ##STR28## with diazomethane or ether toform the corresponding ester which is reacted with triphenylphosphine inthe presence of benzene to form Wittig reagent O ##STR29## which isreacted with aldehyde L' ##STR30## in the presence of butyllithium andtetrahydrofuran to form the ester P ##STR31##

Ester P is then reduced by treatment with hydrogen in the presence ofpalladium on carbon and methanol to form the ester O ##STR32## which ishydrolyzed to the corresponding acid R by treatment with alkali metalhydroxide in the presence of methanol to form acid R ##STR33##

Acid R is converted to the hydroxamate VI ##STR34## employing proceduressimilar to that in converting acid F to hydroxamate IV.

Compounds of the invention wherein Z is ##STR35## that is compounds offormula II may be prepared by reacting Wittig reagent ##STR36## withpyridinecarboxaldehyde S ##STR37## in the presence of potassiumt-amylate and tetrahydrofuran or other solvent such as toluene, to formT ##STR38## (wherein R is a mixture of ##STR39##

Compound T is then hydrogenated to its reduced form which is hydrolyzedand then converted to the hydroxamate II employing procedures as set outhereinbefore.

Compounds of formula I wherein R² is alkyl may be prepared fromcompounds IV, V, VI or VII by treating I with a base such as sodiumhydride and an alkyl halide (Hal-Alkyl) in the presence of an inertorganic solvent such as tetrahydrofuran and dimethylformamide, to formcompounds of the invention VIII ##STR40##

Compounds of formula I wherein R² is alkanoyl or aroyl may be preparedfrom compounds IV, V, VI or VII by treating I with an alkanoyl halide,alkanoyl anhydride or aroyl halide in the presence of an organic basesuch as pyridine to form compounds of the invention IX, where R¹¹ isalkyl or aryl ##STR41##

The compounds of the invention are delta-5-lipoxygenase inhibitors andprevent leukotriene C₄ formation in macrophages (Samuelsson, B.,Science, Vol. 220, p. 568-575, 1983). The administration of compounds ofthis invention to humans or animals provides a method for treatingallergy of a reagin or non-reagin nature. Asthma is preferably treatedbut any allergy wherein leukotrienes are thought to be involved aspharmacological mediators of anaphylaxis can be treated. For example,the compounds of this invention can be used for treatment of suchconditions as allergic rhinitis, food allergy and urticaria as well asasthma, bronchial asthma and asthmoid bronchitis.

An effective but essentially non-toxic quantity of the compound isemployed in treatment.

The compounds of the invention can be administered orally, parenterallyor topically or by aerosol to various mammalian species known to besubject to such maladies, e.g., humans, cattle, horses, cats, dogs, andthe like in an effective amount within the dosage range of from about 1to about 10 mg/kg, preferably from about 1 to about 50 mg/kg andespecially about 2 to about 25 mg/kg on a regimen in single or 2 to 4divided daily doses.

The active substance can be utilized in a composition such as tablet,capsule, solution, cream, lotion, suspension or aerosol containing fromabout 5 to about 500 mg per unit of dosage of a compound or mixture ofcompounds of formula I. They may be compounded in conventional matterwith a physiologically acceptable vehicle or carrier, excipient, binder,preservative, stabilizer, flavor, etc. as called for by acceptedpharmaceutical practice. Also as indicated in the discussion above,certain members additionally serve as intermediates for other members ofthe group.

The following Examples represent preferred embodiments of the invention.Unless otherwise indicated, all temperatures are expressed in °C. TLCplates were visualized by spraying and heating with 5% phosphomolybdicacid in ethanol. HP-20 refers to a high porousdivinylbenzene-polystyrene polymer resin.

EXAMPLE 12-[4-[4-[(N-Hydroxy-N-Methylamino)carbonyl]phenyl]butyl]benzoic acid A.

(1) o-Toluic acid, methyl ester

A mixture of o-toluic acid (15 g, 0.11 mole), iodomethane (51 g, 0.36mole) and anhydrous sodium bicarbonate (25.2 g, 0.3 mole) in drydimethylformamide (60 ml) was stirred at 70° (oil bath temperature)under an atmosphere of nitrogen for 3.5 hours. The resulting mixture wasdiluted with water (200 ml) and extracted with ethyl ether (3×100 ml).The combined extracts were washed several times with water, dried overanhydrous MgSO₄ and evaporated in vacuo to give the title ester compound(15 g, 90.6%) as an oil with a consistent H¹ -NMR spectrum.

(2) α-Bromo-o-toluic acid, methyl ester

A solution of Parts A(1) acid (15 g, 99.88 mmole), N-bromosuccinimide(18.67 g, 104.87 mmole) and azobisisobutyronitrile (250 mg) in 100 ml ofdry benzene was refluxed under an atmosphere of nitrogen for 5 hours andthen cooled to room temperature. The precipitated succinimide wasremoved by filtration. The filtrate was evaporated in vacuo to givetitle ester compound (20.3 g, 88.7%) as a homogeneous (tlc) oil with aconsistent H¹ -NMR spectrum.

(3) [[2-(Methoxycarbonyl)phenyl]methyl]triphenylphosphonium bromide

A solution of Part A(2) ester compound (11.45 g, 50 mmole) andtriphenylphosphine (13.12 g, 50 mmole) in 150 ml of dry acetonitrile wasrefluxed under an atomsphere of nitrogen for 24 hours. The solvent wasevaporated in vacuo. The residue was rinsed with ethyl ether and theether removed by decantation. The resulting solid was dried over P₂ O₅in vacuo at 100° overnight to give title compound (20.2 g, 82.2%) with aconsistent H¹ -NMR spectrum.

B. 4-Hydroxypropylbenzoic acid

To a chilled and stirred solution of diisopropylamine (4.63 ml, 33mmole) in 20 ml of dry tetrahydrofuran at -78° C. (dry ice-acetone bath)under nitrogen was added dropwise 1.7M n-butyllithium in hexane (19.4ml, 33 mmole). After 20 minutes, a solution of p-toluic acid (2.042 g,15 mmole) in 20 ml of dry tetrahydrofuran was added dropwise. Afterstrirring at -78° for another 1.5 hours, HMPA (4 ml) was added and thenimmediately followed by a solution of dry ethylene oxide (2.99 g, 67.9mmole) in 10 ml of dry tetrahydrofuran. The resulting solution wasstirred at -78° for two hours, acidified with 5% hydrochloric acid,warmed up to room temperature and most of the tetrahydrofuran removed invacuo. The aqueous solution was saturated with sodium chloride andextracted with ethyl ether (3×100 ml). The combined ether extracts wereconcentrated to 100 ml and extracted with 0.5N sodium hydroxide solution(2×50 ml). This was acidified with 10% hydrochloric acid and extractedwith ethyl ether (3×100 ml). The ether extracts were dried overanhydrous MgSO₄ and evaporated in vacuo to give a gum. This waschromatographed on a silica gel (120 g, Baker 60-200 mesh) column,eluting successively with dichloromethane-ethyl acetate (9:1 and 1:1),ethyl acetate and dichloromethane-methanol (9:1) to give 750 mg (27.7%solid) of tlc-homogeneous title acid compound with a consistent H¹ -NMRspectrum.

C. 4-Hydroxypropylbenzoic acid, benzyl ester

A mixture of Part B acid compound (1.35 g, 7.49 mmole), benzyl bromide(1.409 g, 8.24 mmole) and anhydrous sodium bicarbonate (1.57 g, 18.75mmole) in 15 ml of dry dimethylformamide was stirred at room temperatureunder an atmosphere of nitrogen overnight. The resulting suspension wasdiluted with water (50 ml) and extracted with ethyl ether (200 ml). Theether extract was washed several times with water, dried over anhydrousMgSO₄ and evaporated in vacuo to give an oil. This was chromatograhed ona silica gel (60 g, Baker 60-200 mesh) column eluting successively withchloroform and chloroform-ethyl acetate (9:1) to give thetlc-homogeneous title ester compound (1.24 g, 61.2%) as an oil with aconsistent H¹ -NMR spectrum.

D. 3-[[4-(Benzyloxycarbonyl)]phenyl]propionaldehyde

To a slurry of HYFLO (3 g, dried in vacuo at 100° overnight), anhydroussodium acetate (290 mg) of pyridinium chlorochromate (4.68 g) in 25 mlof dry dichloromethane was added dropwise a solution of Part C estercompound (1.24 g, 4.59 mmole) at room temperature under an atmosphere ofnitrogen. After stirring for 1.5 hours, the slurry was diluted withethyl ether (100 ml), filtered through a bed of HYFLO and washed withethyl ether (50 ml). The filtrate and the washing were combined andwashed successively with 0.2M KH₂ PO₄ (25 ml), water (25 ml), 5% CuSO₄(25 ml), water (25 ml), 1.0N KHCO₃ (25 ml) and water (25 ml). Theorganic phase was dried over anhydrous MgSO₄ and evaporated in vacuo togive an oil. This was chromatographed on a silica gel (60 g, Baker60-200 mesh) column eluting successively with ethyl acetate-hexane(5:95, 1:9, and 2:8) to give the tlc-homogeneous title aldehyde compound(855 mg, 69.4%) as an oil with a consistent H¹ -NMR spectrum.

E. 2-[4-[4-[(Benzyloxy)carbonyl]phenyl]-1-butenyl]benzoic acid, methylester

To a chilled and stirred suspension of Part A compound (491.35 mg, 1.0mmole) in 8 ml of dry tetrahydrofuran (ice bath) was added dropwisen-BuLi (0.5 ml, 0.8 mmole, 1.6M in hexane) under an atmosphere ofnitrogen. The suspension became a yellow solution. After stirring in theice bath for one hour, a solution of Part D compound (134.2 mg, 0.5mmole) in 2 ml of dry tetrahydrofuran was added dropwise. The solutionwas then stirred at 0° under an atmosphere of nitrogen for another 4hours, acidified with 5% hydrochloric acid to pH=2.5, concentrated invacuo to remove most of the tetrahydrofuran and extracted with ethylether (3×30 ml). The combined ether extracts were washed with brine,dried over anhydrous MgSO₄ and evaporated in vacuo to give an oil (170mg). Another run using 720 mg (2.68 mmole) of Part D compound and 2.64 g(5.37 mmole) of Part A compound gave 1.0 g more of an oily product. Theoils (1.17 g) were combined and chromatographed on a silica gel (100 g,Baker 60-200 mesh) column eluting with ethyl acetate-hexane (5:95) togive title compound (710 mg, 55.7%) as an oil with a consistent H¹ -NMRspectrum.

F. 2-[4-[4 -(Carboxy)phenyl]butyl]benzoic acid, methyl ester

A solution of Part E compound (710 mg, 1.77 mmole) containing asuspension of palladium on carbon (10%, 200 mg) in 80 ml of methanol washydrogenated under atmospheric pressure at room temperature for 2 hoursand the mixture filtered through a bed of HYFLO to remove the catalyst.The filtrate was evaporated in vacuo to give slightly impure titlecompound. This was chromatographed on a silica gel (50 g, Baker 60-200mesh) column eluting successively with chloroform-hexane (9:1) and ethylacetate-chloroform (5:95) to give the tlc-homogeneous title acid-estercompound (463 mg, 83.6%) as a solid, melting point 120°-122°, with aconsistent H¹ -NMR spectrum.

G. 2-[4-[4-(Chloro)carbonyl]phenyl]butylbenzoic acid, methyl ester

To a chilled (0°, ice bath) and stirred solution to Part F acid compound(460 mg, 1.47 mmole) in a mixture of benzene (15 ml) anddimethylformamide (5 drops) was added dropwise oxalyl chloride (1.2 ml,13.76 mmole) under an atmosphere of nitrogen. After the addition wascomplete, the solution was stirred at room temperature for 2 hours. Thesolvent was evaporated by a stream of nitrogen. The residue was dried invacuo at room temperature for one hour to give title acid chloridecompound (478 mg, 98.1%) as a gum. This was unstable to moisture and wasused immediately without characterization.

H. 2-[4-[4-[(N-Hydroxy-N-Methylamino)carbonyl]phenyl]butyl]benzoic acid,methyl ester

To a stirred solution of N-methyl hydroxylamine hydrochloride (362 mg,4.33 mmole) and triethylamine (2 ml, 15 mmole) in a mixture oftetrahydrofuran (10 ml) and water (3 ml) was added dropwise a solutionof Part G acid chloride compound (478 mg, 1.44 mmole) in 10 ml of drytetrahydrofuran. After 2.0 hours, the mixture was acidified with 5%hydrochloric acid to pH=2.5, concentrated in vacuo to remove most of thetetrahydrofuran, saturated with sodium chloride and extracted with ethylether (3×50 ml). The combined ether extracts were dried over anhydrousMgSO₄ and evaporated in vacuo to give 433 mg (87.8%) of title hydroxamicacid compound as an oil with a consistent H¹ -NMR spectrum. It washomogeneous by tlc.

I. 2-[4-[4-[(N-Hydroxy-N-Methylamino)carbonyl]phenyl]butyl]benzoic acid

A solution of Part H hydroxamic acid compound (413 mg, 1.21 mmole) in amixture of methanol (10 ml) and water (1.5 ml) was refluxed with sodiumhydroxide (3M, 1.5 ml) under an atmosphere of nitrogen for 2 hours. Theresulting solution was cooled to room temperature, acidified with 5%hydrochloric acid, concentrated in vacuo to remove most of the solvents,saturated with sodium chloride and extracted with ethyl ether (4×50 ml).The combined ether extracts were dried over anhydrous MgSO₄ andevaporated in vacuo to give a gummy residue. This was chromatographed ona silica gel (30 g, Baker 60-200 mesh) column eluting withdichloromethanemethanol (98:2) to give slightly impure (tlc) titlecompound. Two recrystallizations of this from ethyl ether gave 255 mg(64.4%) of a tlc-homogeneous analytical specimen, m.p. 94°-95° withconsistent mass, IR (1690 cm⁻¹, 1612 cm⁻¹, C═O strong), H¹ -NMR and C¹³-NMR spectral data.

Anal. Calc'd for C₁₉ H₂₁ NO₄ : Calc'd: 69.70; H, 6.47; N, 4.28; Found:69.65; H, 6.51; N, 4.11.

EXAMPLE 24-[4-[4-[(N-Hydroxy-N-Methylamino)carbonyl]phenyl]butyl]benzoic acid A.α-Bromo-p-toluic acid, benzyl ester

A mixture of α-bromo-p-toluic acid (10.75 g, 50 mmole; Aldrich ChemicalCo.), benzyl alcohol (5.4 g, 50 mmole), dicyclohexylcarbidiimide (10.3g, 50 mmole) and 4-dimethylaminopyridine (50 mg) in a mixture of dryether (200 ml) and dry THF (50 ml) was stirred at room temperature for8.0 hours. The resulting solid was removed by filtration and washed withsmall amounts of ether. The filtrate and washings were combined,evaporated and the residue was filtered through a column of silica gel(Baker, 60-200 mesh, 100 g) using Et₂ O-hexane (2:8) for elution toisolate title ester as a homogeneous (tlc) oil (14.0 g, 92%) with aconsistent H¹ -NMR spectrum.

B. [[[4-(Benzyloxy)carbonyl]phenyl]methyl]triphenyl phosphonium bromide

A stirred solution of Part A ester (4.2 g, 13.8 mmole) andtriphenylphosphine (3.6 g, 13.8 mmole) in dry benzene (100 ml) wasrefluxed for 8.0 hours under an atomsphere of nitrogen resulting in theprecipitation of title ester compound. After cooling to roomtemperature, the mixture was filtered, the solid was washed with smallamounts of ether and dried in vacuo to afford title ester compound as acolorless solid (6.9 g, 88.5%).

C. 4-Hydroxypropylbenzoic acid, methyl ester

To a solution of Example 1 Part B acid compound (750 mg, 4.16 mmole) ina mixture of dichloromethane (50 ml) and methanol (10 ml) was added asolution of ethereal diazomethane until the yellow color persisted.After stirring for 30 minutes, the excess diazomethane was destroyed bya few drops of glacial acetic acid. The solvent was evaporated in vacuoto give 800 mg (99.0%, oil) of title ester compound with a consistent H¹-NMR spectrum.

D. 3-[[4-(Methoxycarbonyl)]phenyl]propionaldehyde

To a stirred mixture of pyridinium chlorochromate (6.0 g), dried Celite(6.0 g) and anhydrous sodium acetate (365 mg) in dry chloromethane (30ml) under dry nitrogen was added a solution of Part C ester compound(1.5 g, 7.72 mmole) in dry dichloromethane (20 ml). After 1.75 hours,the mixture was diluted with ether (100 ml). The supernatant wasdecanted and the procedure was repeated once again with ether (100 ml).The combined supernatant solutions were washed successively with 0.2MKH₂ PO₄ (9 ml), H₂ O (9.0 ml), 5% CuSO₄ (9 ml), H₂ O (9.0 ml), 1N KHCO₃(9.0 ml) and H₂ O (9.0 ml), dried (MgSO₄) and evaporated. The residualoil was filtered through a column of silica gel (25 g, Baker 60-200mesh) using Et₂ O-hexane (1:1) for elution to isolate title compound asan oil (1.12 g, 76%) with a consistent H¹ -NMR spectrum.

E. 4-[4-[4-[(Benzyloxy)carbonyl]phenyl]-]1-butenyl]benzoic acid, methylester

To a cooled (ice-bath) and stirred suspension of the Part B phosphoniumsalt (4.4 g, 7.76 mmole) in dry THF (35 ml) was added 1.75M n-BuLi inhexane (4.0 ml, 7.0 mmole). The resulting light red suspension wasstirred for 2.0 hours and a solution of the Part D aldehyde (1.25 g, 6.5mmole) in dry THF (4.0 ml) was added. After 30 minutes, the ice bath wasremoved and the mixture was stirred at room temperature for 4.0 hours.The excess reagent was destroyed by the addition of a few drops ofacetic acid. The mixture was then evaporated to leave a solid. This wasdissolved in the minimum amount of warm ethyl acetate (discarding theinsoluble solids) and applied on a flash-chromatography column (LPS-1silica gel). Elution of the column with EtOAc-hexane (1:9) affordedtitle ester compound as a homogeneous (tlc, silica gel, Rf=0.45;EtOAc-hexane, (1:4) colorless solid (2.1 g,; 81%) with a consistent H¹-NMR spectrum).

F. 4-[4-[4-(Carboxy)phenyl]butyl]benzoic acid, methyl ester

A solution of Part E acid compound (1.35 g, 3.37 mmole) in methanol (150ml, warmed to dissolve and cooled to room temperature) containing 5%Pd/C (30 mg) was stirred under an atmosphere of hydrogen for 1.5 hours.The mixture was then filtered through a bed of Celite, washing theCelite with small amounts of methanol. The filtrate and the washingswere combined and evaporated to afford title acid compound as a solid(1.0 g, 95%) with consistent H¹ - and C¹³ -NMR spectral data. It washomogeneous by tlc (Rf=0.38, silica gel, CH₃ OHCHCl₃ 5:95) and can becrystallized from EtOAc or EtOAc-hexane.

G. 4-[4-[4-[(N-Hydroxy-N-Methylamino)carbonyl]phenyl]butyl]benzoic acid,methyl ester

To a cooled (ice-bath) and stirred suspension of the Part F acid (1.0 g,3.21 mmole) in benzene (10 ml) and chloroform (10 ml) was addedoxalylchloride (1.0 ml) followed dropwise by a solution of DMF (0.2 ml)in benzene (1.0 ml). After stirring at room temperature for 1.0 hour,most of the solvents were removed under a jet of nitrogen and theresidue was dried in vacuo (50°, 0.5 hour, 0.3 mm). The residual acidchloride was dissolved in dry THF (5.0 ml) and added into a chilled(ice-bath) and stirred solution of CH₃ NHOH.1HCl (535 mg, 6.4 mmole) andEt₃ N (1.77 ml, 12.8 mmole) in 75% THF (20 ml). The mixture was thenwarmed to room temperature, evaporated in vacuo, diluted with brine (50ml) and 10% hydrochloric acid (15 ml) and extracted with ethyl acetate(3×50 ml). The extracts were combined, washed with brine (2×20 ml),dried (MgSO₄ anhydrous) and evaporated to afford a solid (1.1 g). Onecrystallization of this from ethyl acetate-hexane gave a specimen oftitle hydroxamic acid (900 mg, 83%), m.p. 123°-124°, with consistentH¹ - and C¹³ -NMR spectral data.

H. 4-[4-[4-[(N-Hydroxy-N-Methylamino)carbonyl]phenyl]butyl]benzoic acid

A solution of Part G hydroxamic acid compound (850 mg, 2.49 mmole) inmethanol (30 ml) containing water (5.0 ml) and 3M NaOH (2.5 ml) wasrefluxed under an atmosphere of nitrogen for 30 minutes. It was thencooled to room temperature, acidified and concentrated in vacuo. Theconcentrate was diluted with water, the solids present were isolated byfiltration, washed with water (2×10 ml) and dried to afford the titlecompound as a powder (800 mg, 98.2%). One crystallization of this fromethyl acetate followed by drying (80°, 0.3 mm, 4.0 hours) gave ananalytical specimen of title compound as a homogeneous (tlc) colorlesssolid (670 mg, 81%), m.p. 165°-166° with consistent mass, IR (1674 cm⁻¹,1610 cm⁻¹, 1600 cm⁻¹, all strong, C═O), H¹ -NMR and C¹³ -NMR spectraldata.

Anal. Calc'd for C₁₉ H₂₁ NO₄ : Calc'd: C, 69.70; H, 6.47; N, 4.29;Found: C, 69.61; H, 6.46; N, 4.24.

EXAMPLE 3 N-Hydroxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide A.4-(3-Bromopropyl)benzoic acid

A gummy complex of triphenyl phosphine (3.16 g, 12 mmole) andN-bromosuccinimide (2.14 g, 12 mmole) was prepared by stirring inbenzene (35 ml) in an ice bath for 10 minutes and at room temperaturefor 1.0 hour. A solution of 4-(3-hydroxypropyl)benzoic acid (1.08 g, 6.0mmole) in dry CH₂ Cl₂ (15 ml) was added and the stirring was continuedfor 30 minutes. The mixture was then concentrated in vacuo, diluted withEt₂ O (50 ml) and a solution of sodium carbonate (1.27 g, 12 mmole) inwater (50 ml) and stirred vigorously. The Et₂ O layer was then separatedand the aqueous layer was extracted once again with Et₂ O (30 ml). Theextracts were discarded. The aqueous layer was acidified with 10%hydrochloric acid and extracted with Et₂ O (2×30 ml). The extracts werecombined, washed with water (2×10 ml), dried (MgSO₄ anhydrous) andevaporated to afford the title compound which was slightly impure (tlc).It was chromatographed on a column of silica gel (Baker 60-200 mesh, 25g), eluting the column with hexane and Et₂ O-hexane mixtures (1:4, 1:3,1:1) to isolate the title compound as a colorless solid (1.2 g, 83%).One crystallization from Et₂ O-hexane gave 1.0 g, m.p. 116°-117°. The H¹-NMR spectrum was consistent with the structure.

B. 4-(3-Bromopropyl)benzoic acid, methyl ester

To a solution of 1.0 g (4.10 mmole) of Part A acid compound in 100 ml ofdichloromethane was added an ethereal solution of diazomethane until theyellow color of the solution persisted. The solution was stirred for 30minutes and the excess diazomethane was destroyed by a few drops ofglacial acetic acid. The solvent was evaporated in vacuo to give thetlc-homogeneous title compound (1.05 g, 99.6%, oil) with a consistent H¹-NMR spectrum.

C. [3-[4-(Methoxycarbonyl)phenyl]propyl]triphenyl phosphonium bromide

A mixture of Part B ester compound (1.05 g, 4.08 mmole) andtriphenylphosphine (1.07 g, 4.08 mmole) in 20 ml of dry acetonitrile wasrefluxed under nitrogen for 24 hours. The solvent was evaporated by astream of nitrogen. The gummy residue was rinsed with ethyl ether (2×50ml). The ether was decanted and the gummy residue solidified. The whitesolid was dried at 75° over P₂ O₅ in vacuo overnight to give titlecompound (1.57 g, 74.1%) with a consistent H¹ -NMR spectrum.

D. 4-[4-(4-Pyridinyl)-2-butenyl]benzoic acid, methyl ester

and

E. 4-[4-(4-Pyridinyl)-2-butenyl]benzoic acid, t-amyl ester

A stirred suspension of Part C compound (1.56 g, 3 mmole) in 20 ml ofdry tetrahydrofuran was cooled to 0° (ice-water bath) under nitrogen andthen a solution of K-t-amylate (1.7M in toluene) was added dropwise. Thesuspension became an orange-red solution. This was warmed to roomtemperature, stirred for 30 minutes and rechilled to 0°. A solution of4-pyridinecarboxaldehyde (257 mg, 2.4 mmole) in 2 ml of drytetrahydrofuran was added dropwise. The solution was gradually warmed upto room temperature, stirred for 2 hours and the pH was adjusted to 5.5with 5% hydrochloric acid. The tetrahydrofuran was mostly removed invacuo. The residue was diluted with 20 ml of water, saturated withsodium chloride and extracted with ethyl ether (3×50 ml). The combinedether extracts were dried over anhydrous MgSO₄ and evaporated in vacuoto give an oil. This was chromatographed on a silica gel (100 g, Baker60-200 mesh) column, eluting successively with chloroform, ethylacetate-chloroform (1:1) and ethyl acetate to give 720 mg (oil) of titlecompounds. On the basis of H¹ -NMR spectrum, it was a mixture of themethyl and t-amyl esters.

F. 4-[4-(4-Pyridinyl)butyl]benzoic acid, methyl ester

and

G. 4-[4-(4-Pyridinyl)butyl]benzoic acid, t-amyl ester

A mixture of Part D and E compounds (720 mg) and 10% palladium on carbon(200 mg) in 40 ml of methanol was hydrogenated at room temperature underatmospheric pressure for 1.5 hours. The resulting solution was filteredthrough a bed of HYFLO and washed with a small amount of methanol. Thefiltrate and washing were evaporated in vacuo to give 720 mg of titlecompound as an oil. On the basis of H¹ -NMR spectrum (the olefinicprotons had disappeared), it was a mixture of the methyl and t-amylesters.

H. 4-[4-(4-Pyridinyl)butyl]benzoic acid

A mixture of Parts F and G compounds (720 mg) and 3M sodium hydroxidesolution (5 ml) in a mixture of methanol (20 ml) and water (1 ml) wasrefluxed for 5 hours under an atmosphere of nitrogen. The methanol wasremoved in vacuo. The residue was diluted with water (25 ml) andextracted with ethyl ether to remove non-acidic impurities. The pH ofthe aqueous solution was adjusted to 5.5 with 5% hydrochloric acid. Theprecipitated solid was filtered off, washed with a small amount of waterand dried at 100° over P₂ O₅ in vacuo overnight to give 406 mg of titleacid compound as a solid with a consistent H¹ -NMR spectrum.

I. 4-[4-(4-Pyridyl)butyl]benzoyl chloride

To a stirred and chilled (0°, water ice bath) suspension of Part H acidcompound (300 mg, 1.175 mmole) in a mixture of dry benzene (10 ml) anddimethylformamide (3 drops) was added dropwise oxalyl chloride (1.03 ml,11.75 mmole) under nitrogen. After the addition was complete, themixture was stirred at room temperature for 5 hours. The solvent wasevaporated by a stream of nitrogen and the residue was dried in vacuo atroom temperature for one hour to give 305 mg (89.6%) of title acidchloride compound as a solid. This was unstable to moisture and usedimmediately without characterization.

J. N-Hydroxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide

To a stirred solution of N-methylhydroxylamine hydrochloride (264 mg,3.16 mmole) and triethylamine (0.9 ml, 6.46 mmole) in a mixture oftetrahydrofuran (6 ml) and water (2ml) was added dropwise a solution ofPart I acid chloride compound (305 mg, 1.053 mmole) under nitrogen.After stirring overnight at room temperature, the pH of the solution wasadjusted to 5.5 with 5% hydrochloric acid. The tetrahydrofuran wasmostly removed in vacuo. The residue was extracted with dichloromethane(2×50 ml). The combined dichloromethane extracts were dried overanhydrous MgSO₄ and evaporated in vacuo to give a solid. This waschromatographed on a silica gel (40 g, Baker 60-200 mesh) column elutingsuccessively with dichloromethane and methanol-dichloromethane (2:98) togive 235 mg of title compound. Crystallization fromdichloromethane-hexane gave 185 mg (61.8%) of the tlc-homogeneousanalytical specimen, m.p. 148°-150°, with consistent MS, IR (1610 cm⁻¹,C=O, strong; 3431 cm⁻¹, OH, strong), H¹ -NMR and C¹³ -NMR spectral data.

Anal. Calc'd for C₁₇ H₂₀ N₂ O₂ with 0.34 mole water; Calc'd: C, 70.30;H, 7.18; N, 9.64; Found: C, 70.30; H, 7.04; N, 9.49.

EXAMPLE 4 4,4'-(1,4-Butanediyl)bis(N-hydroxy-N-methylbenzamide) A.[[[4-(Methoxy)carbonyl]phenyl]methyl]triphenyl phosphonium bromide

A suspension of α-bromo p-toluic acid (5.0 g, 23.3 mmole) in ether (75ml) was treated with an excess amount of diazomethane in ether andstirred at room temperature for 2 hours. The excess diazomethane wasblown off with a stream of nitrogen and the colorless solutionconcentrated down to an oil which was chromatographed (gravity) on asilica gel column (Baker, 60-200 mesh, 200 ml). The column was elutedwith ether-hexane mixtures (1:9, 1:4) and the fractions containing thedesired product were combined and evaporated to dryness. The residualester (5.38 g, 23.3 mmole) and triphenylphosphine (6.17 g, 23.3 mmole)were refluxed in benzene (170 ml) for 8 hours under nitrogen and cooled.The white precipitates obtained were filtered off, washed with a smallamount of ether and dried in vacuo (pump) for 5 hours to give titlecompound as a solid (10.49 g, 91.6%) with a consistent H¹ -NMR spectrum.

B. 4-[4-[4-(Methoxy)carbonyl]phenyl]-2-butenyl benzoic acid, methylester

A cooled (ice-bath) suspension of Part A compound (2.14 g, 4.35 mmole,1.19 equiv.) and 1.6M n-butyllithium (2.45 ml, 3.92 mmole, 1.08 equiv.)in dry tetrahydrofuran (20 ml) was stirred at 0° under nitrogen for 2hours. The reddish-orange suspension was then treated with a solution of##STR42## (prepared as described in Example 2 Part D) in drytetrahydrofuran (3 ml), stirred at 0° for 30 minutes then at roomtemperature for 2.5 hours. The mixture was treated dropwise with glacialacetic acid until the yellow color disappeared and evaporated todryness. The residual solid was triturated with warm ethyl acetate (75ml) and filtered, washing the insoluble precipitates with a small amountof ethyl acetate. The filtrate was evaporated and the semi-solidobtained was chromatographed (flash) on a silica gel column to give thetitle compound as a liquid (694.3 mg, 58.8%) with consistent H¹ - andC¹³ -NMR spectral data.

C. 4-[4-[4-(Methoxy)carbonyl]phenyl]butyl benzoic acid, methyl ester

A solution of Part B compound (694.3 mg, 2.14 mmole) in dry methanol(100 ml) was treated with 5% Pd/c (20 mg) and hydrogenated at roomtemperature for 2 hours. The suspension was filtered through a Celitepad and the filtrate evaporated to give title compound as a homogeneous(tlc) oil (690.6 mg, 98.9%) with consistent H¹ - and C¹³ -NMR spectraldata.

D. 4,4'-(1,4-Butanediyl)bis-benzoic acid

A solution of Part C compound (690.6 mg, 2.12 mmole) in methanol (25 ml)and water (4 ml) was treated with 50% NaOH (0.5 ml, 6.24 mmole) andrefluxed under nitrogen for 1.5 hours. The reaction mixture was cooled,diluted with water (25 ml) and acidified with 2.5N HCl (3.3 ml). Themethanol was evaporated off and the aqueous slurry extracted twice withdichloromethane (50 ml). The organic phase was washed with brine (20ml), dried (anhydrous MgSO₄), filtered and evaporated to dryness. Thecrude product was recrystallized from a combined solution of ethylacetate and methanol to give title compound as a homogeneous (tlc) solid(516.4 mg, 81.6%, m.p. 275°-280°).

E. 4,4'-(1,4-Butanediyl)bis(N-hydroxy-N-methylbenzamide)

A solution of Part D compound (516 mg, 1.73 mmole) in dry benzene (20ml) was cooled down to 0° and treated with oxalyl chloride (4 ml)followed by a solution of dimethylformamide (3 drops) in dry benzene(2.0 ml). The mixture was stirred at 0° for ˜10 minutes then at roomtemperature for one hour. The excess oxalyl chloride and benzene wereblown off with a stream of nitrogen in a warm bath and the residue wasdried in vacuo (pump) for one hour.

The above acid chloride was dissolved in dry tetrahydrofuran (10 ml) andadded to a cooled (ice-water bath) solution of methylhydroxylaminehydrochloride (1.18 g) and triethylamine (3.82 ml, 16 equiv.) intetrahydrofuran (8 ml) and water (8 ml). The mixture was stirred at 0°for 30 minutes, at room temperature for 3.5 hours, diluted with water(60 ml) and adjusted to pH 5.0 with 2.5N HCl (˜5.5 ml). The aqueoussolution was extracted three times with dichloromethane (150 ml) and theorganic extract was washed with brine (50 ml), dried (anhydrous MgSO₄),filtered and evaporated to dryness. The crude product showed twocarbonyl peaks, one due to carboxylic acid, by infrared spectroscopy, sothe entire amount (690 mg) was dissolved in dichloromethane (250 ml)containing some methanol, washed several times with saturated NaHCO₃solution and brine (25 ml). The organic phase was dried (anhydrousMgSO₄) and evaporated to give title compound as a colorless solid (350mg, 56.8%, m.p. 157°-159°) after drying in vacuo (0.5 mm) at 60° for 18hours, with consistent analytical, MS, IR (1597 cm⁻¹, strong, C=O, 3162cm⁻¹, strong, OH), H¹ - and C¹³ -NMR spectrum.

EXAMPLE 5 3-[4-[4-[(Hydroxymethylamino)carbonyl]phenyl]butyl]benzoicacid

By following the procedure of Example 1, but replacing o-toluic acidwith m-toluic acid in Part A(1), the title compound can be prepared.

EXAMPLE 6 N-Acetyloxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide

A solution of 200 mg ofN-hydroxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide in dry pyridine(3.0 ml) was mixed with acetic anhydride (0.5 ml) and was allowed tostand at room temperature for 20 hours. The mixture was thenconcentrated in vacuo, diluted with dichloromethane, washed with adilute Na₂ CO₃ solution and water, dried (MgSO₄ anhydrous), evaporatedand the residue was purified by column chromatography on silica gel toafford the title compound.

EXAMPLE 7 N-Benzoyloxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide

By following the procedure of Example 6 but replacing acetic anhydridewith benzoyl chloride and carrying out the reaction at a lowertemperature (0°), the title compound can be prepared.

EXAMPLES 8 to 26

Following the procedures outlined in the specification and the workingExamples, the following exemplary compounds in accordance with thepresent invention may be prepared.

    __________________________________________________________________________     ##STR43##                                                                    Ex. No.                                                                             Z (position)    m  R.sup.1     R.sup.2                                  __________________________________________________________________________     8.                                                                                  ##STR44##      3  H           CH.sub.3                                  9.                                                                                  ##STR45##      4  C.sub.2 H.sub.5                                                                            ##STR46##                               10.                                                                                  ##STR47##      5  C.sub.6 H.sub.5                                                                           C.sub.2 H.sub.5                                 ##STR48##      6  CHCHCH.sub.3                                                                              H                                        12                                                                                   ##STR49##      3                                                                                 ##STR50##  CH.sub.3                                 13                                                                                   ##STR51##      5                                                                                 ##STR52##                                                                                 ##STR53##                                      ##STR54##      7  H           H                                               ##STR55##      8  C.sub.3 H.sub.7                                                                            ##STR56##                                      ##STR57##      4  C.sub.6 H.sub.5                                                                           CH.sub.3                                        ##STR58##      6  CH.sub.2CHCHCH.sub.3                                                                      C.sub.2 H.sub.5                                 ##STR59##      8                                                                                 ##STR60##  C.sub.4 H.sub.9                                 ##STR61##      2                                                                                 ##STR62##                                                                                 ##STR63##                               20.                                                                                  ##STR64##      3  (CH.sub.2).sub.2                                                                          H                                               ##STR65##      6  CHCHCH.sub.3                                                                              H                                               ##STR66##      3                                                                                 ##STR67##  CH.sub.3                                        ##STR68##      5                                                                                 ##STR69##                                                                                 ##STR70##                                      ##STR71##      7  H                                                                                          ##STR72##                                      ##STR73##      8  C.sub.3 H.sub.7                                                                            ##STR74##                                      ##STR75##      4  C.sub.6 H.sub.5                                                                           CH.sub.3                                 __________________________________________________________________________

What is claimed is:
 1. A compound having the structure ##STR76## whereinR¹ is H, alkyl, aryl, lower alkenyl having 3 to 8 carbons, cycloalkylhaving 3 to 12 carbons, or aryl-alkyl;R² is H, alkyl, aryl, cycloalkylhaving 3 to 12 carbons, alkanoyl or aroyl; m is 2 to 8; ##STR77##wherein R³ is COOH; and (CH₂)_(m) is unsubstituted or substituted with 1or 2 alkyl and/or 1 or 2 halogen substituents; and where Z is ##STR78##including pharmaceutically acceptable basic salts thereof, wherein theterm alkyl by itself or as part of another group is a straight chain orbranched chain radical having 1 to 12 carbons and is unsubstituted orsubstituted with halogen, CF₃, alkoxy, aryl, alkyl-aryl, haloaryl,cycloalkyl, alkylcycloalkyl, hydroxy, alkylamino, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol or alkylthio; and the term arylby itself or as part of another group is a monocyclic or bicyclicaromatic group having 6 to 10 carbons in the ring portion and isunsubstituted or substituted with 1 or 2 alkyl groups, 1 or 2 halogens,1 or 2 alkoxy groups, an aryl group, 1 or 2 hydroxy groups, 1 or 2alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2 arylcarbonylaminogroups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1or 2 thiol groups and/or 1 or 2 alkylthio groups.
 2. The compound asdefined in claim 1 wherein R¹ is alkyl.
 3. The compound as defined inclaim 1 wherein R¹ is alkyl and R² is H.
 4. The compound as defined inclaim 1 wherein Z is ##STR79##
 5. The compound as defined in claim 4wherein R³ is o- or p-CO₂ H.
 6. The compound as defined in claim 1wherein Z is ##STR80##
 7. The compound as defined in claim 1 having thename N-hydroxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide.
 8. Thecompound as defined in claim 1 having the name2-[4-[4-[(N-hydroxy-N-methylamino)carbonyl]phenyl]butyl]benzoic acid. 9.The compound as defined in claim 1 having the name4-[4-[4-[(N-hydroxy-N-methylamino)carbonyl]phenyl]butyl]benzoic acid.10. A composition for inhibiting allergic conditions in a mammalianspecies, comprising an effective amount of a compound as defined inclaim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier therefor.
 11. A method of treatingallergy of a reagin or non-reagin nature, which comprises administeringto the circulatory system of a mammalian host an effective amount of acompound as defined in claim 1 or a pharmaceutically acceptable saltthereof.
 12. The method as defined in claim 11 wherein said compound isadministered in an amount within the range of from about 1 to about 100mg/kg.
 13. A method for treating asthma in a mammalian species in needof such treatment, which comprises administering to a mammalian host aneffective amount of a compound as defined in claim 1 or apharmaceutically acceptable salt thereof.